Process Study On The Closedloop Synthesis Of Theophylline Sodium Salt By 1,3-Dimethylformylaminourazine

Theophylline sodium salt is a white powdered alkaloid,which is widely used in many fields such as medicine and food,and industrial synthetic production is its main source.In recent years,as the demand for caffeine as a central nervous system stimulant in the domestic and international markets grows year by year,the theophylline sodium salt,which is an important intermediate in the synthesis of caffeine,can no longer meet the market demand.The current production process of theophylline sodium salt is mostly an intermittent process,which has the disadvantages of low production efficiency,poor product color and waste of large of raw materials,and is in urgent need of technological upgrading.Therefore,in this thesis,a series of research works were carried out for the closed-loop synthesis of theophylline sodium salt by 1,3-dimethylformylaminouracil(dimethyl FAU)process.To address the shortcomings of the theophylline sodium salt synthesis process such as high alkali consumption,low product yield and many impurities.The current closedloop reaction yield of dimethyl FAU is around 89%～91%.Based on this,a closed-loop reaction optimization experiment for the synthesis of theophylline sodium salt from dimethyl FAU was carried out under the alkaline environment provided by sodium hydroxide(Na OH)solution.The effects of dimethyl FAU to Na OH molar ratio,reaction temperature,initial concentration of dimethyl FAU,mass fraction of Na OH solution and the way of Na OH solution dosing on the yield and selectivity of the closed-loop reaction were investigated.The initial optimization of the closed-loop reaction was carried out by orthogonal tests,and then the factors affecting the product yield and selectivity were further optimized by single-factor experiments,and the optimal process conditions were finally obtained as follows: dimethyl FAU to Na OH molar ratio=1:1.4,reaction temperature 85℃,initial concentration of dimethyl FAU 11%,mass fraction of Na OH solution 15%,and the better Na OH solution The dosing method was a one-time addition of dimethyl FAU after it reached 85℃.Under these conditions,the average yield of the sodium salt of theophylline was 97.83% and the average selectivity was 97.87% as measured by three validation experiments.The solubility data of the sodium salt of theophylline in different concentrations of Na OH solutions over a certain temperature range were determined by the equilibrium method.The solubility data were fitted using the polynomial empirical equation,the simplified Apelblat equation and the λh equation.The experimental results showed that the solubility of the sodium salt of theophylline increased with the increase of temperature in the same concentration of Na OH solution;the solubility of the sodium salt of theophylline decreased with the increase of Na OH concentration at the same temperature.These solubility data correlated well with the polynomial empirical equation,the simplified Apelblat equation and the λh equation,while the thermodynamic properties of theophylline sodium salt in Na OH solutions of different concentrations,such as enthalpy of dissolution,entropy of dissolution and Gibbs free energy change,were estimated using the modified Van’t Hoff equation.The solubility data and correlation results obtained from the experiments can provide basic data for the continuousization,separation and purification,and mother liquor recovery processes of theophylline sodium salts,which are of great significance for the production and R&D of theophylline sodium salts.The analytical method and conditions for the determination of fluorescent substances in closed-loop reaction solution were established.By comparing the results of the spectrophotometric method and the high performance liquid chromatographic method for the analysis of the closed-loop reaction solution samples,it was determined that the high performance liquid chromatographic method was a better method for the determination of fluorescent substances in the closed-loop reaction solution,and the excitation wavelength of 250 nm and the scanning wavelength range of 300～650 nm were used for the fluorescence detection after testing.The high temperature of 100～130℃and four extractants of dichloromethane,ethyl ether,trichloromethane and methyl cyclohexane were used to treat the reaction solution after the closed-loop reaction of dimethyl FAU,and the effect of high temperature and extraction on the removal of fluorescent substances from the closed-loop reaction solution was studied.It was found that the above two methods have good effect on the removal of fluorescent substances from the closed-loop reaction solution and can be used in industrial production.